Process for preparing 3-[N&#39;-(3-halopropyl)-N&#39;-methylamino]-N,N,N-trimethyl-1-propanaminium halide

ABSTRACT

Novel linear, unbranched, non-cross-linked polymers particularly poly-[{methyl-(3-trimethylammoniopropyl)iminio}trimethylene dihalide] are prepared by the polymerization of the novel monomer, 3-[N&#39;-(3-halopropyl)-N&#39;-methylamino]-N,N,N-trimethyl-1-propanaminium halide, or an acid addition salt thereof preferably in an oxygen excluded environment, e.g., under nitrogen or argon. The polymer, especially after modification of terminal groups, is an excellent oral anticholesterolemic.

This is a division of application Ser. No. 570,910, filed Apr. 23, 1975,now U.S. Pat. No. 4,016,209, issued Apr. 5, 1977.

DISCLOSURE OF THE INVENTION

This invention relates to novel linear, non-cross-linked, non-branchedpolymers and their preparation by the polymerization of a novel monomer.The term "non-branched" is intended herein to indicate a polymer havingno repeated monomer units extending from the polymer backbone; the termlinear is intended to define a polymer having a straight chain and theterm "non-cross-linked" is used in its usual sense.

More particularly, this invention relates to the preparation of a3-[N'-(3-halopropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumcompound of the formula: ##STR1## where X is chloro, bromo, or iodo, Yis a pharmaceutically acceptable anion and preferably is chloride,bromide or iodide and is most preferably the same as X, together withacid addition salts thereof. According to Chemical Abstractsnomenclature, a compound of Formula I is a3-[(3-halopropyl)methylamino]-N,N,N-trimethyl-1-propanaminium.

In the compounds of formula I, a is the anionic charge on Y, m being anumber such that the product of m and a is 1.

This invention is also concerned with the polymer prepared from monomerI, which is apoly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene] compoundhaving the structural formula: ##STR2## WHERE Y, m, and a are as abovedefined; n is an integer such that the number average molecular weightof polymer II is greater than about 2,000; and W is 3-halopropyl,3-hydroxypropyl, or allyl. The proportion of end groups W that are3-halopropyl, 3-hydroxypropyl, or allyl varies and depends upon theconditions of the polymerization reaction since the latter willdetermine the extent and nature of the displacement of the chloro moietyof the end groups.

As reaction time or temperature increase, the proportion ofhydroxypropyl end groups or allyl end groups compared to halopropyl endgroups likewise increases. Conversely, with the shorter reaction timesor with lower reaction temperatures the proportion of halo end groupsdisplaced is decreased.

Generally, there can be from about 10 to 80% by weight of polymer IIterminating in hydroxypropyl and from 5 to 90% terminating inhalopropyl, any remainder being the allyl terminal group. Thehydroxypropyl end group is satisfactory from a utility standpoint, butis not a wholly desired moiety since it represents a terminal polymergroup that cannot undergo further polymerization during reaction withmonomer I, and therefore prematurely terminates chain growth.Termination in a halopropyl group is termination in a group whichpotentially can undergo further chain growth, but for exhaustion ofmonomer I or other reasons. The allyl group represents elimination of HXand likewise is a terminal group that can undergo no furtherpolymerization. In essence then these three species are the result ofrandomly occurring reactions during polymerization of monomer I.

This invention is particularly concerned with the end group modifiedpolymer III in which the 3-halopropyl end groups have been modified bydisplacement of the halo moiety by hydrogen, alkylthio ortriloweralkylammonio functions. Said end group modified polymer preparedfrom polymer II is apoly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene] compoundhaving the structural formula: ##STR3## where Y, m, n, and a are asdefined above and Z may be 3-trimethylammoniopropyl associated with oneequivalent of Y^(a) counter anion, 3-(2-naphthylthio)propyl,3-benzenethiopropyl, 3-hydroxypropyl, propyl or allyl. The proportion ofend groups Z that are 3-hydroxypropyl or allyl is largely dependent uponthe nature of the end groups W in the precursor polymer II. In preferredembodiments of polymer III n is generally greater than 10 so that thenumber average molecular weight is from about 4,000 to 16,000, althoughthe molecular weight of individual species can range from 600 to 20,000.The molecular weight of polymers II and III is established by thetitration of the unique tertiary amine end group, by gel permeationchromatography and measurement of intrinsic viscosity. As determined bytitration, rather consistent number average molecular weights of about5,000 are obtained, whereas gel permeation indicates average molecularweights of about 14,000 and higher.

Polymers II and III are useful as antistatic agents, antimicrobialagents, flocculating agents, agents for coating paper to render itelectroconductive, and nonabsorbable gastrointestinal bile acid bindingagents. This latter property makes polymers II and III particularlyvaluable since the sequestration of bile acids in man is known to reducelevels of blood serum cholesterol. Because of their water solubility andtheir linear, unbranched, non-cross-linked structure and their highcharge to mass ratio, polymers II and III are the most efficient bileacid sequestrants available. Polymer III is particularly noteworthy inthis respect since its end groups Z make it safer and more acceptablepharmaceutically for chronic administration to lower blood serumcholesterol levels.

All available evidence indicates that the incidence of higher thannormal blood serum cholesterol levels in humans (especially in so-calledType II Frederickson patients) is associated with atherosclerosis andother hypercholesteremic disease signs. Atherosclerosis is manifested bythe effects of occlusion of the circulation, giving rise to coronary,cerebrovascular, and some forms of peripheral vascular diseases and itis the leading cause of death in many countries.

In an effort the reduce the incidence of atherosclerosis, elevated bloodserum cholesterol levels are the target of various control measures,including restricted and special dietary intake, inhibition ofcholesterol synthesis, accelerated catabolism, prevention ofgastrointestinal absorption, as well as by means of binding bile acidsin the gastrointestinal tract. This latter technique is highly favoredsince it requires neither surgical intervention nor sudden and severechanges in dietary habits or lifestyle of patients.

The exact means by which gastrointestinal bile acid binding accomplishesa lowering of blood serum cholesterol levels is, however, unknown; it isbelieved feedback mechanisms effect cholesterol oxidation responsesdepleting serum cholesterol in an effort to restore bile acid levels.Regardless of the uncertainty of its mechanism, the technique is wellaccepted. What is lacking is a convenient, efficient, non-toxic, andeasily tolerated binding agent.

Heretofore, a variety of bile acid binding agents have been employed.These include iron salts which produce insoluble precipitates with bileacids, organic bases to act similarly, and polymers having asalt-forming capability. Absorbable precipitants, however, present acuteand chronic toxicity hazards. The use of non-absorbable highlycrosslinked polymers to avoid such toxicity problems has not provided asuitable alternative, because the average effective adult daily dose ofsuch polymers heretofore employed ranges up to 40 grams; thecross-linking effectively prevents access to a large number of potentialbinding sites and drastically reduces efficiency. The physical bulk ofsuch a dose, especially when of a water-insoluble cross-linked resin,can induce partial blockage of the gastrointestinal tract and anunpleasant, heavy sensation. Furthermore, any objectionable odor andtaste of so large a dose is difficult to mask.

Gel-type compositions which have less cross-linking and are branched, asthat term is heretofore defined, swell markedly on water sorption, andalthough relatively free of abrasive irritation, often cause pressurediscomfort.

Water-soluble polymers heretofore proposed for use as bile acid bindingagents cause very high viscosities in solution, and have markedastringent action in the oral cavity. Furthermore, they present muchbulk for consumption, retaining as much as an equal weight of water indry form. Most seriously, they can be degraded in the gastrointestinaltract.

Consequently, there has been only limited benefit derived from treatmentby this method, although the incidence of disease linked tohypercholesteremia is extremely high and continues to rise alarmingly.

Several explanations are advanced for the inability of resins heretoforesuggested for use in hypercholesterolemics to match bile acid uptakewith the efficiency of chloride ion capture. One view holds that smallerinorganic anions can reach binding sites more readily than the bile acidanion. Therefore, to make a more efficient resin one should providegreater separation of binding sites to accommodate bulky acids. Anotherview holds that resins need to be more lipid-like to penetrate in vivomicelle formations holding fat-like bile acids, thus leading tosuggestions that decreased water solubility for resins was desirable.

Unfortunately, these concepts have produced little improvement whentranslated into polymer design for treating hypercholesterolemia.

We now find that the polymers of this invention are exceptionallyefficient agents for treating hypercholesterolemia and have theextremely important advantage that their end groups present no knowntoxicity potential.

Monomer I is synthesized by one of the following three alternativemethods.

It is most suitably obtained by the following route.3-Bromo-N,N,N-trimethyl-1-propanaminium halide is reacted withmethylamine in an inert solvent, e.g., alkanols such as ethanol ormethanol, dimethylformamide, water or mixtures thereof at temperaturesfrom 0° C. to 30° C. for from 4 to 24 hours. The term inert solvent usedin this and following instances signifies that the solvent does notreact with the other reactants or products thereof.

The product N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium halidehydrobromide is suspended in a suitably inert solvent, preferablymethanol, ethanol or water, and an equivalent of base, preferably analkali or alkaline earth hydroxide or alkali carbonate is added slowlyduring a period of from 10 minutes to 5 hours. The temperature ismaintained at 0° C. to 50° C. during the addition of alkali. Thereaction mixture is concentrated to dryness under reduced pressure, andthe product N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium halide isextracted from the residue with a suitable solvent such as acetonitrile.

The product N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium halide maybe purified by recrystallization from an alkanol solvent mixture, e.g.,isopropanoldiethyl ether or it may be used without further purificationin the next step in which it is treated in aqueous solution with from1.1 to 3 equivalents of oxetane in a sealed vessel at a temperature offrom 50° C. to 150° C. for a period of from 10 to 24 hours. The productis isolated by concentration of the reaction mixture to dryness andextraction into a suitable solvent such as acetonitrile from which itcrystallizes on evaporation of the solvent. The product, 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumhalide may be purified by recrystallization from acetonitrile.

Prior to the conversion of the 3-hydroxypropyl function to a3-halopropyl moiety, the intermediate3-[N'-3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumhalide may be suitably converted to a propanaminium analog. Mostpreferably this analog bears the same halide counter anion as the halomoiety that will displace the hydroxyl function of the hydroxypropylmoiety, although other counter anions Y^(a) are suitable. The conversionis accomplished by passing an aqueous solution of the 1-propanaminiumhalide intermediate acidified with an appropriate acid through anappropriate anion exchange resin in the desired anionic form.

Alternatively, the halide anion of the intermediate may be exchanged forOH⁻, which in turn may be acidified with HY or exchanged for Y^(a) bypassage of an appropriately neutralized solution through an anionexchange resin on the y^(a) cycle.

Concentration of the aqueous eluate to dryness yields the desiredintermediate, which on treatment with an appropriate halogenating agentsuch as thionyl chloride, phosphorus oxychloride, phosphoruspentachloride, thionyl bromide or phosphorus pentabromide yields a3-[N'-(3-halo-propyl)-N'-methylamino]1-propanaminium halide acidaddition salt. The product is usually purified by concentration of thereaction mixture and leaching of the residue with an appropriate ethersolvent. The residue is taken up in water, and the solution is treatedwith activated carbon. The aqueous solution is then filtered andconcentrated to dryness under reduced pressure and crystallized from amixed solvent such as isopropanol-acetone.

In a second alternative process, monomer I may be synthesized in onestep by treating N,N,N-trimethyl-[3-(methylamino)]-1-propanaminiumhalide with one equivalent of a 1,3-dihalotrimethylene compound such as3-chloro-1-iodopropane, 3-bromo-1-chloropropane, or 1,3-dibromopropane,in an inert solvent such as acetonitrile. Insoluble by-products areremoved by filtration, the reaction mixture is concentrated to dryness,and the product is extracted from the residue with an appropriatesolvent such as chloroform or methylene chloride. Counter anion exchangemay be accomplished as described above and the product may becrystallized from isopropanol-ether or isopropanol-acetone mixtures.

In a third alternative synthesis of monomer I, 3-aminopropanol is addedto acrylonitrile yielding 3-(2-cyanoethyl)aminopropanol, which in turnis converted in two steps to 3-[N-(2-cyanoethyl)-N-formylamino]propanol.The nitrile function of the latter is catalytically reduced to a primaryamine function which in turn is exhaustively alkylated with a methylhalide to yield a3-[N'-formyl-N'-(3-hydroxypropyl)amino]-N,N,N-trimethyl-1-propanaminiumhalide. Reduction of the formyl moiety in the latter to a methylfunction is accomplished by treating this intermediate with a formicacid-formalin mixture at 60° C.-100° C. for 10-24 hours, followed byacidification with the appropriate aqueous hydrogen halide andconcentration to dryness yielding a3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumhalide hydrohalide. Conversion of this intermediate to3-[N'-(3-halopropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumhalide hydrohalide is accomplished as described in our preferredsynthesis of monomer I above, and anion exchange, if desired, iseffected by any of the heretofore described procedures.

Polymer II is obtained through the head to tail polymerization ofmonomer I, preferably in an oxygen excluding environment by thetreatment of an acid addition salt of monomer I with one equivalent ofan aqueous alkali hydroxide or by the polymerization of monomer I as afree base in aqueous solution. Generally, if the acid addition salt ofmonomer I is employed, the bulk of the resulting neutralization salt isremoved prior to polymerization. The polymerization is itself conductedin an aqueous medium usually 3 to 10 molar in monomer I. The reactionmedium comprising monomer I and water is heated in an oxygen excludingatmosphere, usually under nitrogen or argon, to a temperature of from80° C.-110° C. for a period of from 6 to 60 hours. Temperatures inexcess of 100° C. can be employed with pressurization techniques. Thereaction is most preferably conducted at 100° C. with a 6-8 molaraqueous solution of monomer I for 12-18 hours under nitrogen. Theproduct is rid of salt and low molecular weight materials byultrafiltration of a 5% aqueous solution in Amicon Filter Cells equippedwith UM10 Diaflow® Ultrafilters at constant volume and 60 psi pressure.The purified polymer is isolated from the aqueous retentate byconcentration under reduced pressure at temperatures up to 50° C. Theproduct is usually ground to a fine powder and dried under reducedpressure over phosphoric anhydride.

The remaining chloro end groups of polymer II are displaced by one ofthree methods to yield polymer III. These conversions are carried out inaqueous solution and preferably at room temperature or lower to minimizepartial degradation of the polymer that might occur in alkaline reactionmedia. For conversion of the 3-chloropropyl end group to a3-trimethylammoniopropyl halide end group, polymer II is dissolved in asmall amount of water and treated for 8 to 24 hours with a large excessof 6M trimethylamine in water. The product is isolated by concentrationof the reaction medium to dryness at reduced pressure and temperaturesnot exceeding 30° C. The product may be ground to a powder and driedunder reduced pressure or it may be subjected to a preliminarypurification by ultrafiltration of a 5% aqueous solution of the isolatedpolymer followed by concentration of the retentate to dryness underreduced pressure.

Alternatively, the chloro moiety of the 3-chloro-propyl end groups ofpolymer II may be displaced by naphthylthio or benzenethio moieties inaqueous solution. An aqueous solution of the polymer is treated with upto a two-fold excess of the sodium salt of either a naphthylthiol orbenzenethiol at room temperature for from 12 to 48 hours. Next an amountof acid equivalent to the sodium mercaptide is added and the unreactedthiol reagent is removed by filtration or extraction of the reactionmedium with an appropriate solvent such as diethyl ether or chloroform.The aqueous solution of polymer III is usually purified byultrafiltration, concentration of the retentate under reduced pressure,and drying over phosphoric anhydride under reduced pressure.

For the displacement of the chloro end group of polymer II by hydrogen,an aqueous solution of polymer II and two equivalents of a base isreduced over a noble metal catalyst at room temperature until theappropriate hydrogen uptake is recorded. Potassium acetate is apreferred base and 5% palladium on carbon is a preferred catalyst toeffect the conversion. In general, a reaction time of two days isrequired for reductions carried out at 40 psi of hydrogen. The productis usually purified by ultrafiltration and changes in counteranioncomposition owing to the base used are adjusted by passage of theretentate through a column of Dowex 1 X-2 anion exchange resin on theappropriate anion cycle. The product is usually isolated byconcentration of the aqueous solution to dryness under reduced pressure.

The anions on polymers II and III are generally limited to halide by thetechniques of the prior steps. The full range of polymers where theanion differs from halide can be obtained by dissolving polymer II orIII having a halide anion in water, alcohol, or mixtures thereof in anyproportion and passing the solution through a bed of anion exchangeresin, either a synthetic or a zeolite type, where the halide ion isexchanged and replaced by Y^(a). The anion exchange method employing aresin technique can be direct, that is, exchanging halide ion for Y^(a)or one can first exchange halide ion for OH⁻ and then either by asubsequent ion exchange or simple neutralization, exchange OH⁻ forY^(a).

Additionally, chemical exchange techniques can be employed when aprecipitate of a metal halide is less soluble than the added slightlysoluble metal salt MY. The precipitated metal halide can then befiltered from the soluble polymer II or III.

A simple example of the latter technique involves treating a solution ofpolymer II or III containing the bromide counter ion with an excess offreshly precipitated silver chloride. After the halide anion exchange iscomplete, the mixture of silver chloride and silver bromide is removedby filtration leaving a solution of polymer II or III containing thechloride counter ion. Alternatively, polymer II or III where Y^(a) issulfate can be treated with solutions of water soluble calcium or bariumsalts. Thus, sulfate can be replaced with nitrate and the precipitate ofbarium sulfate removed.

Throughout this description, Y^(a) represents an anion which countersthe charge on the quaternized imino group, and thus can be a monovalentanion. It is to be understood, however, that Y^(a) is contemplated toinclude polyvalent anions where one anion can counter the charge on morethan one charged imino group. Thus, Y^(a) can include anions ofinorganic acids, as well as of organic acids such as, for example,halide, e.g., chloride, bromide, or iodide; sulfate; bisulfate;phosphate; acetate; ascorbate; citrate; hydroxycitrate; carbonate;bicarbonate; nicotinate; glycinate; taurinate; salicylate; and otheranions derived from physiologically non-toxic acids, especially salts ofphysiologically active acids such as those derived from clofibrate andhalofenate, i.e., 2-(p-chlorophenoxy)-2-methylpropionic and3-trifluoromethylphenoxy-(4-chlorophenyl)-acetic acids. When such anionsof physiologically active compounds are used to neutralize quaternizedimino groups, it is apparent that only a portion of the charged iminogroups may be so neutralized. The amount of anion from thephysiologically active compound is apportioned in a ratio such that theamount administered with the polymer dosage can fall within the desiredrange for the physiologically active compound.

Effective lowering of cholesterol blood levels is obtained by the oraladministration of remarkably small dosages of the polymers of thisinvention. This enables a flexibility of formulation previouslyunavailable. The polymers can be finely divided powders and suitablyused as such or preferably admixed with varying amounts of solid carrieragents such as colloidal silica, starches, sucrose, talc, lactose,cellulose, or modified cellulose, dry milk powder, protein powders suchas soy flour, and the like. These are preferably made into unit dosageforms such as tablets, filled gelatin capsules or a foil or paperenvelope containing the premeasured dose which can include supplementaryvitamins and minerals, and which can be readily torn open and added toedible liquids such as fruit juices or other beverages. The unit dosecomposition may comprise from 10% to 99% by weight of polymer, theremainder being carriers, flavorings, excipients, flow agents and thelike. In such a unit dose, the active polymer may comprise from 0.1 gm.to up to 10 gms. in powder packets.

Also suitable are aqueous solutions or suspensions which can be preparedand are preferably sweetened or flavored. Although not entirelydesirable, the polymers can be mixed in various vehicles such assafflower or corn oil for oral ingestion as such or as an aqueousemulsion. These may also be encapsulated.

The total daily dosage of bile acid binding polymer is preferablydivided into three or four equal portions and taken before each meal andprior to bedtime. This regimen provides for maximum resin contact timeduring periods of highest intestinal bile acid concentrations.

The polymers of this invention may be used alone, or, if desired, can becompounded together with triglyceride synthesis inhibitors or other bileacid binding agents for particular treatments. In addition, asheretofore stated, the polymers described herein form salts with theacids of clofibrate and halofenate, which salts are useful incardiovascular disease therapy. The following examples are illustrativeof the dosage forms which can be employed in the practice of ourinvention. Those skilled in the art of pharmaceutical compounding willbe aware of variations which can be practical without departing from thespirit of our invention. It is anticipated that multiple dosages, e.g.,two or three tablets or capsules can be taken at one time if higherdosages are prescribed.

Additional ingredients which may comprise the carrier portion of thecompositions of this invention, can also have pharmacological activityand can include other choleretic agents such as tocamphyl florantyrone;taurine; and glycine; hypocholesteremic agents such as nicotinic acid;the D-isomer of 3,3'5-triiodothyronine; thyroxine-like compounds such assodium L-thyroxin and sodium D-thyroxine; triiodothyropropionic acid;nafoxidine hydrochloride, 5-methylpyrazole-3-carboxylic acid and3-methyl-5-isoxazolecarboxylic acid; fecal softeners such as poloxalkoland dioctyl sodium sulfosuccinate; as well as unsaturated fatty acidssuch as linoleic acid, arachidonic acid and linolenic acid. Although notpreferred, edible vegetable oils such as corn oil and safflower oil arealso suitable.

POWDER PACKETS

Linear, unbranched and non-cross-linkedpoly[{methyl-(3-trimethylammoniopropyl)imino}trimethylene dichloride] isfinely powdered and blended with 1% by weight of lactose powder.Aluminum envelopes containing a paper bag liner are individually filledwith 0.55 g. of the mixture and sealed against moisture to preventcaking.

HARD GELATIN CAPSULES

A 250 mg. dose ofpoly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene dichloride]containing 1% by weight of lactose as described above is filled into theappropriate size hard gelatin capsules.

Alternatively, a dry filled capsule can be prepared from the followingcomponents:

    ______________________________________                                        poly-[{(methyl-3-trimethylammoniopropyl)imino}-                                                          300    mg.                                         trimethylene dichloride]                                                      corn starch                150    mg.                                         cab-o-sil (anhydrous silica)                                                                             5      mg.                                         ______________________________________                                    

If capsules of lower potency are to be prepared, the capsule size can bedecreased or additional corn starch or other diluent employed. Whenusing smaller amounts of active ingredient it is anticipated that amultiple capsule dose can be administered.

COMPRESSED TABLETS

A dry blend is prepared with the following components:

    ______________________________________                                        poly-[{(methyl-(3-trimethylammoniopropyl)imino}-                                                         1      kg.                                         trimethylene dichloride]                                                      sucrose, powdered          30     gms.                                        collidal silica            10     gms.                                        carbowax-4000              30     gms.                                        ______________________________________                                    

Four thousand tablets are pressed therefrom by direct compression eachof which tablets contains 250 mg. of the ionene polymer.

Likewise, compressed tablets are prepared such that each tabletcontains:

    ______________________________________                                        poly-[{(methyl-(3-trimethylammoniopropyl)imino}-                                                         300    mg.                                         trimethylene dichloride]                                                      corn starch                30     mg.                                         polyvinylpyrrolidone       10     mg.                                         magnesium stearate         3      mg.                                         ______________________________________                                    

After tabletting, a plastic film can be applied to the tablets to sealthem from moisture in ways well known in the art. tableting

In addition, an enteric coating may be applied, if desired. Such acoating may comprise fats, fatty acids, waxes and mixtures thereof,shellac, ammoniated shellac, and cellulose acid phthalates applied bytechniques well known and accepted.

In place of thepoly-[{(methyl-3-trimethylammoniopropyl)imino}trimethylene dichloride],there may be substituted and the other polymer salts of our invention.

Other binding agents may be used in place of sucrose, such as dextrose,lactose, methyl cellulose, natural and synthetic gums, and the like.Talc can replace the calcium or magnesium stearate. A variety of readilyavailable non-toxic anti-caking agents may be substituted for thecolloidal silica.

Other lubricants, diluents, binders, coloring agents, flavoring agentsand disintegrators can be used as are known in the art employing wet ordry granulation techniques, direct compression, spray drying, and thelike.

If desired, a chewable tablet can be prepared from preferablymicroencapsulated polymer particles by dry granulation as follows:

    ______________________________________                                        microencapsulated poly-[{(methyl-(3-trimethyl-                                                           750    mg.                                         ammoniopropyl)imino}trimethylene dichloride]                                  mannitol                   300    mg.                                         sodium saccharine (or other sweetener)                                                                   2      mg.                                         oil of peppermint          1      mg.                                         carbowax-4000              15     mg.                                         microcrystalline cellulose 100    mg.                                         ______________________________________                                    

All of the above dosage forms are administered orally in an effectivebile acid binding dose. For lowering blood serum cholesterol levels,generally a single or multiple dose of from about 0.1 to 5.0 grams issuitable although doses in excess of 10 grams can be given whereindicated. Such doses are also effective in relieving symptoms ofbiliary pruritus. Administration can be in a variety of forms, such as asuspension, in an aqueous solution, as a chewable or a coated tablet, orin a capsule, and can be continued for an extended course of treatment.Generally, medication is on a daily basis with each day's dose taken individed portions, preferably with meals.

For control of hypercholesterolemia, the particular individual dosage,given variances in metabolism and diet, is preferably arrived at throughan initial determination and continued monitoring of blood serumcholesterol levels. Thus, a moderate dosage might be employed initially,and increased until the desired blood serum cholesterol level isachieved and maintained. For an initial dose, pending such individualadjustment, from 2.5 to 100 mg./kg. of body weight per day issatisfactory.

It is contemplated that acid addition salts of monomer I, as well asacid addition salts of polymer II and III, including those salts derivedfrm the acids H_(l/m) Y^(a). where Y, m and a are as above defined areequally well suited for the uses heretofore described.

The followingexamples are included as illustrative of the invention andare not intended to limit the scope of the invention as described in theforegoing specification and claims.

EXAMPLE 1 STEP 1 N,N,N-Trimethyl-[3-(methylamino)]-1-propanaminiumBromide Hydrobromide

To a stirred solution of 40% aqueous methylamine 229.57 g. (7.4 moles)cooled in an ice-water bath is added in three equal portions a solutionof 3-bromo-N,N,N-trimethyl-1-propanaminium bromide (452.66 g., 1.78moles) in 400 ml. of distilled water over a period of forty minutes. Theice-water bath is removed and the mixture is stirred for 4.0 hours.After this time the reaction mixture is evaporated under reducedpressure and the crystalline residue is dried in vacuo.Recrystallization of the residue from absolute ethanol gives 442.62 g.(87.6%) of product; m.p. 185°-189° (dec.); NMR (D₂ O) δ: 2.76 (3H, S,--N⁺ H₂ CH₃); 3.16 (9H, S, --N⁺ 3)₃).

Analysis calculated for C₇ H₂₀ N₂ Br₂ : C, 28.79; H, 6.90; N, 9.59; Br,54.72.

Found: C, 28.63; H, 7.27; N, 9.47; Br, 54.49.

STEP 2 N,N,N-Trimethyl-[3-(methylamino)]-1-propanaminium Bromide

To a stirred suspension of 876.0 g. (3.0 moles) ofN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide hydrobromidein 2.75 liters of absolute methanol at room temperature is added afreshly prepared solution of sodium hydroxide (120.0 g., 3.0 moles) in1.0 liter of absolute methanol over a period of 1.0 hour. The reactionmixture is evaporated under reduced pressure and the solid residue isshaken with 750 ml. of acetonitrile. The insoluble sodium bromide isremoved by filtration and the filtrate is evaporated. The solid residueis dried in vacuo to give a quantitative yield of white, crystallinehygroscopic product which may be used without further purification orcan be recrystallized from isopropanol-ether. NMR (D₂ O)δ: 2.28 (3H, S,--NHCH₃); 3.11 (9H, S, --N⁺ (CH₃)₃).

STEP 33-[N'-(3-Hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumBromide

A mixture of 20 g. of oxetane (0.34 mole), 32.8 g. ofN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide (0.156 mole)and 22 ml. water is heated in a sealed tube at 100° for 15 hours. Thesolution is evaporated in vacuo and the residue is dissolved in 50 ml.of acetonitrile and filtered. Upon evaporation the desired productcrystallizes. The product may be recrystallized from acetonitrile.

Analysis calculated for C₁₀ H₂₅ N₂ OBr: C, 44.61; H, 9.36; N, 10.41; Br,29.68.

Found: C, 44.59; H, 9.02; N, 10.27; Br, 29.84.

STEP 43-[N'-(3-Chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumChloride Hydrochloride

A sample of 44.4 g. of product from Step 3,3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumbromide, is dissolved in 500 ml. of water and acidified to pH 2 withconcentrated hydrochloric acid. The solution is passed through a columnof Dowex 1-X2 chloride form ion exchange resin and the eluant isevaporated under reduced pressure. The residual viscous oil is dried invacuo and treated with thionyl chloride (25 ml.) added dropwise withstirring during one hour. The solution is heated at 50° for 1.5 hoursand then evaporated under reduced pressure.

The residue is washed with ether (2 × 200 ml.) and dried in vacuo. Thecrude product is dissolved in 100 ml. of water and 0.5 g. of charcoal isadded. The mixture is heated to boiling and stirred while hot for onehour. After being filtered through Celite, the filtrate is evaporatedunder reduced pressure. To the residue is added 40 ml. of isopropanol,which is evaporated. Another 40 ml. of isopropanol is added and theevaporation is repeated until 10 ml. of isopropanol remains. At thispoint, 100 ml. acetone is added and the product is crystallized. Thesolid is chopped to a fine powder and collected by suction filtration.The solid is washed with 3:1/acetone: isopropanol (2 × 90 ml.) andacetone (90 ml.). The product is recrystallized from1:2/isopropanol-acetone to give 30 g. of desired product. Furtherpurification provided the analytical sample.

Analysis calculated for C₁₀ H₂₅ N₂ Cl₂ : C, 42.95; H, 9.01; N, 10.02;Cl, 38.03.

Found C, 43.07; H, 9.30; N, 10.01; Cl, 38.15.

EXAMPLE 23-[N'-(3-Chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumIodide

To a stirred solution of 216.2 mg. (1 mmole) ofN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 1.5 ml. ofacetonitrile is added a solution of 205 mg. (1 mmole) of3-iodo-1-chloropropane in 0.5 ml. of acetonitrile. The mixture isstirred at room temperature for 2.0 hours and the insolubleN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide hydrobromideis removed by filtration. The filtrate is evaporated and the solidresidue obtained is extracted with methylene chloride. The methylenechloride extract is evaporated to give the oily product which isrecrystallized from isopropanol-ether to afford 90 mg. (52%) of product;m.p. 93° (dec.); NMR δ: 2.2 (3H, S, --NCH₃); 3.46 (9H, S, --N⁺ Me₃).

Analysis calculated for C₁₀ H₂₄ N₂ ClI: C, 35.89; H, 7.23; N, 8.37; Cl,10.59.

Found: C, 35.75; H, 7.39; N, 8.36; Cl, 10.20.

EXAMPLE 33-[N'-(3-Chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumBromide

To a stirred solution of 3.02 g. (14.3 mmoles) ofN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. ofacetonitrile is added a solution of 2.25 g. (14.3 mmoles) of3-bromo-1-chloropropane and the mixture is stirred at room temperatureunder nitrogen for 3.5 hours. The mixture is cooled in an ice-water bathand then the insoluble material is removed by filtration. The filtrateis evaporated and dried in vacuo and is extracted with chloroform. Thechloroform extract is evaporated and dried to give 2.05 g. (100%) ofoily product; NMR δ: 2.2 (3H, S, --NCH₃); 3.43 (9H, S, --N⁺ (CH₃)₃).

EXAMPLE 43-[N'-(3-Iodopropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumIodide

To a stirred solution of 216.2 mg. (1 mmole) ofN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 1.5 ml. ofacetonitrile is added a solution of 296 mg. (1 mmole) of1,3-diiodopropane in 0.5 ml. of acetonitrile. The mixture is stirred atroom temperature for 2.0 hours and the insolubleN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide hydrobromideis removed by filtration. The filtrate is evaporated and the solidresidue obtained is extracted with methylene chloride. The methylenechloride extract is evaporated to give the oily product which isrecrystallized from isopropanol-ether.

EXAMPLE 53-[N'-(3-Bromopropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumBromide

To a stirred solution of 3.02 g. (14.3 mmoles) ofN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. ofacetonitrile is added a solution of 2.88 g. (14.3 mmoles) of1,3-dibromopropane and the mixture is stirred at room temperature undernitrogen for 3.5 hours. The mixture is cooled in an ice-water bath andthen the insoluble material is removed by filtration. The filtrate isevaporated and dried in vacuo and is extracted with chloroform. Thechloroform extract is evaporated and dried to give the product.

EXAMPLE 6 STEP 1 3-(2-Cyanoethyl)aminopropanol

A solution of 75 g. (1 mole) of 3-aminopropanol is stirred while 54 g.(1 mole) of acrylonitrile is added dropwise. After being allowed tostand at room temperature for several hours and preferably overnight,the reaction mixture is concentrated under reduced pressure at 50°yielding 3-(2-cyanoethyl)aminopropanol.

STEP 2 Formate Ester of 3-[N-(2-Cyanoethyl)-N-formylamino]propanol

A solution of 127.7 g. of 3-(2-cyanoethyl)aminopropanol in 1 liter of99% formic acid is heated at 85° for 15 hours. The reaction mixture isconcentrated under reduced pressure at 80° and the residue is taken upin 60 ml. of methylene chloride-ethyl acetate (1:1). A 1500 g. silicagel G column packed in methylene chloride-ethyl acetate is prepared, andthe product is purified by adsorption on silica gel G followed byelution using the 1:1 methylene chloride-ethyl acetate system.Concentration of the combined eluates yields the formate ester of3-[N-(2-cyanoethyl)-N-formylamino]propanol.

STEP 3 3-[N-(2-Cyanoethyl)-N-formylamino]propanol

A solution of 55.7 g. of the formate ester of3-[N-(2-cyanoethyl)-N-formylamino]propanol in 300 ml. of methanol istreated with 820 mg. of sodium methoxide at room temperature. After 30minutes, the reaction mixture is concentrated to dryness under reducedpressure and the residue is taken up in 500 ml. of methylene chloride.The methylene chloride solution is filtered and the filtrate isconcentrated under reduced pressure yielding3-[N-(2-cyanoethyl)-N-formylamino]propanol.

STEP 4 3-[N'-Formyl-N'-(3-hydroxypropyl)amino]-1-propanaminium Chloride

A solution of 15.6 g. (100 mmoles) of3-[N-(2-cyanoethyl)-N-formylamino]-propanol in 225 ml. of water istreated with 100 ml. of 1 N hydrochloric acid and reduced over 3.8 g. ofplatinum at room temperature and 40 psi of hydrogen. The reactionmixture is filtered and concentrated under reduced pressure yielding3-[N'-formyl-N'-(3-hydroxypropyl)amino]-1-propanaminium chloride.

STEP 53-[N'-Formyl-N'-(3-hydroxypropyl)amino]-N,N,N-trimethyl-1-propanaminiumChloride

To a suspension of 3.6 g. of3-[N'-formyl-N'-(3-hydroxypropyl)amino]-1-propanaminium chloride in 25ml. of dimethylformamide is added 10.7 g. of anhydrous sodium carbonateand 33 g. (15 ml.) of iodomethane. The mixture begins to reflux gently.When the initial reaction appears to have subsided, the mixture isstirred and heated at 50° for eighteen hours. The reaction mixture isfiltered and the filter cake is washed with 3 × 10 ml. portions ofdimethylformamide. The combined filtrate and washes is concentrated todryness under reduced pressure and the residue is taken up in methanoland concentrated to dryness under reduced pressure. The residue istriturated with hot isopropanol and the mixture is filtered. The productis converted to the chloride-ion-containing product by passage of a 5%aqueous solution of the iodidecontaining product through a column ofAG1-X2 ion-exchange resin (Cl⁻ cycle) and concentrating the aqueouseluate.

STEP 63-[N'-(3-Hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumChloride Hydrochloride

A mixture of 2 g. of3-[N'-formyl-N'-(3-hydroxypropyl)amino]-N,N,N-trimethyl-1-propanaminiumchloride 4 g. of 99% formic acid and 2 ml. of formalin is stirred andheated at 100° for seventeen hours. To the cooled mixture is added 11ml. of concentrated hydrochloric acid and the reaction mixture isconcentrated under reduced pressure. The product is taken up in 35 ml.of 1 N hydrochloric acid and the solution is filtered and concentratedto dryness under reduced pressure yielding3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumchloride hydrochloride.

EXAMPLE 7 Poly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylenedichloride]

13.25 Grams (47.4 mmoles) of3-[N'-(3-chloropropyl-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumchloride hydrochloride is treated in the cold and under nitrogen with8.0 ml. of 5.92 N sodium hydroxide (47.4 mmoles). The pH of the mixtureis adjusted to 11.9 by the addition of 1 N hydrochloric acid and thesolution is separated from salt by centrifugation. The supernatant istransferred to a three-neck flask equipped with a condenser, stirrer andinert gas inlet, and the mixture is stirred and heated to 100° under anitrogen blanket for eighteen hours.

The reaction mixture is diluted to a 200 ml. volume and the solution isplaced in an Amicon Filter Cell equipped with a UM 10 DiafloUltrafilter. The solution is ultrafiltered at 60 psi until the chlorideion content of the ultrafiltrate is negligible. After 1000 ml. ofultrafiltrate is collected, the retentate is concentrated under reducedpressure and the residue is dried to yield 9.4 g. (81%) ofpoly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene dichloride].

EXAMPLE 8 Poly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylenedibromide]

1.689 Grams (4.09 mmoles) of3-[N'-(3-bromopropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumbromide hydrobromide is treated in the cold and under nitrogen with 0.67ml. of 6N sodium hydroxide. The mixture is centrifuged, and thesupernatant phase is transferred to a sealed tube and heated at 100° for10 hours in a nitrogen atmosphere. The reaction mixture is diluted to a100 ml. volume, and the solution is placed in an Amicon Filter Cellequipped with a UM Diaflo Ultrafilter. The solution is ultrafiltered atconstant volume and 60 psi pressure until the ultrafiltrate gives anegative test for halide (400 ml.). The retentate is concentrated todryness under reduced pressure yielding 340 mg. ofpoly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene dibromide].

EXAMPLE 9 Poly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylenechloride iodide]

A solution of 7.15 g. (21 mmoles) of3-[N'-(3-chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumiodide in 3.5 ml. of oxygen-free water is heated at 100° under an argonblanket for eithteen hours. The reaction mixture is diluted to a 150 ml.volume, and the solution is placed in an Amicon Filter Cell equippedwith a UM 10 Diaflo Ultrafilter. The ultrafiltration is carried out atconstant volume and 60 psi pressure. After 900 ml. of ultrafiltrate iscollected, the retentate is concentrated at reduced pressure yielding4.2 g. of poly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylenechloride iodide].

EXAMPLE 10 Poly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylenediiodide]

A solution of 2.55 g. (6 mmoles) of3-[N'-(3-iodopropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumiodide in 1 ml. of oxygen-free water is heated in a sealed tube andunder a nitrogen blanket at 100° for twenty hours. The reaction mixtureis diluted to a 200 ml. volume with water, and the solution is placed inan Amicon Filter Cell equipped with a UM 10 Diaflo Ultrafilter andultrafiltered at constant volume and 60 psi pressure until 1200 ml. ofultrafiltrate is collected. The retentate is concentrated under reducedpressure yielding 1.68 g. ofpoly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene diiodide].

EXAMPLE 11 Poly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylenechloride bromide]

3.69 Grams (10 mmoles) of3-[N'-(3-chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumbromide hydrobromide is treated with 1.7 ml. of 5.92 N sodium hydroxidein the cold and under nitrogen and the pH is adjusted to 11.9 by theaddition of 1 N hydrochloric acid. The mixture is stirred and heated at100° for 18 hours under a nitrogen blanket.

The reaction mixture is diluted to a 100 ml. volume with water andplaced in an Amicon Filter Cell equipped with a UM 10 Diaflo Ultrafilterand ultrafiltered at constant volume and 60 psi pressure until theultrafiltrate gives a negative test for halide (600 ml.). The retentateis concentrated under reduced pressure yielding 1.5 g. ofpoly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene chloridebromide].

EXAMPLE 12 Catalytic Conversion of Polymer Chloropropyl End Group toPropyl

A mixture of 5.0 g.poly-[{methyl-(3-trimethylammoniopropyl)imino}trimethylene dichloride]bearing chloropropyl end groups (MW by titration = 2546, 2.0 mmoles),0.5 g. 5% palladium on carbon, 0.446 g. (4.56 mmoles) of potassiumacetate and 30 ml. water is shaken in a Parr apparatus under 40 psihydrogen pressure for 40 hours at 22°. The mixture is filtered through asintered funnel containing Supercel to remove catalyst. The filtrate isultrafiltered (UM 2 ultrafilter) to remove low molecular weightmolecules and the retentate is evaporated to dryness yielding theproduct. Molecular weight of this material (determined by end grouptitration) = 3042.

For analysis, an aliquot of 1.21 g. of the reduction product isdissolved in 8 ml. water and the solution is acidified to pH 4 with 1%nitric acid. Excess silver nitrate solution is added and theprecipitated silver chloride is removed by centrifugation. The filtrateis passed through Supercel and then ultrafiltered through an AmiconDiaflo UM 2 ultrafilter. The retentate is concentrated under reducedpressure to give 0.943 g. product, which is analyzed for chlorinecontent.

Analysis calculated for ionic Cl, 0; covalent Cl, 0%.

Found: ionic Cl, 0%; covalent Cl, 0%.

EXAMPLE 13 Conversion of Polymer Terminal Chloropropyl Moiety to2-Naphthylthiopropyl

A mixture of 154.6 mg. of sodium hydroxide and 650.6 mg. of2-naphthylmercaptan in 3 ml. water is stirred for 0.5 hour at 22°. Solidpoly-[methyl-(3-trimethylammoniopropyl)imino trimethylene dichloride]bearing terminal chloropropyl moieties (2.548 g., MW by end grouptitration = 2546) and 7 ml. water are added and stirring is continuedfor 24 hours. The mixture is filtered and the filtrate is made up to a50 ml. volume with water and placed in an Amicon Filter Cell equippedwith a UM 10 Diaflo Ultrafilter. After 600 ml. of ultrafiltrate iscollected, the retentate is concentrated to dryness at reduced pressureyielding polymer containing 2-naphthylthiopropyl end groups.

In place of 2-naphthylmercaptan there can be employed an analogousquantity of methylmercaptan, ethylmercaptan, 3-propylmercaptan,2-propylmercaptan and 4-butylmercaptan.

EXAMPLE 14 Conversion of the Polymer Chloropropyl Terminal Group toBenzenethiopropyl

A solution of 3.8 g. of poly-[methyl-(3-trimethylammoniopropyl)iminotrimethylene dichloride] bearing chloropropyl terminal groups in 6 ml.of water is purged with nitrogen and 441 mg. (0.41 ml.) of benzenethioland 4 ml. of 1N sodium hydroxide is added. The mixture is stirred undera nitrogen blanket at room temperature for 24 to 40 hours. The mixtureis then treated with 5 ml. of 1N hydrochloric acid and extracted threetimes with 30 ml. portions of ether. The aqueous phase is concentratedto dryness under reduced pressure yielding 3.7 g. of product that isdissolved in 100 ml. of water and ultrafiltered through a UM 2 DiafloUltrafilter at constant volume and a pressure of 60 psi. After 1200 ml.of ultrafiltrate is collected, the retentate is concentrated to drynessunder reduced pressure yielding 3.27 g. of polymer in which the3-chloropropyl end groups are converted to 3-benzenethiopropyl endgroups.

EXAMPLE 15 Conversion of the Polymer Chloropropyl End Groups toTrimethylammoniopropyl

A solution of 2.7 g. of poly-[methyl-(3-trimethylammoniopropyl)iminotrimethylene dichloride] bearing chloropropyl terminal groups in 5 ml.of water is treated with 25 ml. of aqueous 6.4 M trimethylamine at roomtemperature. After 24 hours, the reaction mixture is concentrated todryness at 30° C. and reduced pressure. The product is either ground toa powder and dried under reduced pressure or dissolved in 50 ml. ofwater and ultrafiltered through a UM 2 Diaflo Ultrafilter at constantvolume and a pressure of 60 psi until trimethylamine is no longerdetected in the ultrafiltrate. Concentration of the retentate underreduced pressure yields 2.7 g. of product in which the 3-chloropropylend groups are converted to 3-trimethylaminopropyl end groups.

Similarly, other triloweralkylamines such as triethylamine,tripropylamine, tributylamine can also be employed as well as mixturesof the various triloweralkylamines.

What is claimed is:
 1. The process which comprises reactingN,N,N-trimethyl-[3-(methylamino)]-1-propanaminium halide with oxetane at50° C. to about 100° C. to produce3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N,-trimethyl-1-propanaminiumhalide, converting the latter compound to its hydrohalide, and reactingthis3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumhalide hydrohalide with thionyl chloride to form3-[N'-(3-chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumhalide hydrohalide.
 2. The process, according to claim 1, whichcomprises reacting N,N,N-trimethyl-[3-(methylamino)]-1-propanaminiumbromide with oxetane in aqueous solution at a temperature of about 100°C., thereby forming3[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumbromide, reacting the latter compound with aqueous hydrochloric acid toform3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumchloride hydrochloride, and reacting the said3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumchloride hydrochloride with thionyl chloride to form3-[N'-(3-chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminiumchloride hydrochloride.